Trajkovic-Bodennec Selena, Bodennec Jacques, Futerman Anthony H
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Blood Cells Mol Dis. 2004 Jul-Aug;33(1):77-82. doi: 10.1016/j.bcmd.2004.03.001.
Gaucher disease is caused by defective activity of acid-beta-glucosidase (GlcCerase), resulting in accumulation of glucosylceramide (GlcCer) mainly in macrophages. We now demonstrate that secondary biochemical pathways regulating levels of phospholipid metabolism are altered in a Gaucher disease macrophage model. Upon treatment of macrophages with the GlcCerase inhibitor, conduritol-B-epoxide, phosphatidylcholine (PC) labeling with the metabolic precursor, [methyl-14C]choline, was elevated after 6 or 12 days in macrophages but not in lymphocytes. These changes correlated with increases in the cytoplasmic/nuclear ratio and with levels of [3H]GlcCer accumulation. Moreover, metabolic labeling with L-[3-3H]serine and L-[methyl-3H]methionine demonstrated that PC synthesis via the methylation of phosphatidylethanolamine is also increased in CBE-treated macrophages. Since PC is a major structural component of biological membranes and the source of various second messengers, we suggest that changes in its metabolism in macrophages may be relevant for understanding Gaucher disease pathology.
戈谢病是由酸性β-葡萄糖苷酶(葡糖脑苷脂酶)活性缺陷引起的,导致葡糖神经酰胺(GlcCer)主要在巨噬细胞中蓄积。我们现在证明,在戈谢病巨噬细胞模型中,调节磷脂代谢水平的次级生化途径发生了改变。在用葡糖脑苷脂酶抑制剂环硫醇-B-环氧化物处理巨噬细胞后,巨噬细胞在用代谢前体[甲基-14C]胆碱标记磷脂酰胆碱(PC)时,6天或12天后PC水平升高,但淋巴细胞中未升高。这些变化与细胞质/细胞核比率的增加以及[3H]GlcCer蓄积水平相关。此外,用L-[3-3H]丝氨酸和L-[甲基-3H]甲硫氨酸进行代谢标记表明,在经环硫醇-B-环氧化物处理的巨噬细胞中,通过磷脂酰乙醇胺甲基化合成PC的过程也增加了。由于PC是生物膜的主要结构成分以及各种第二信使的来源,我们认为巨噬细胞中其代谢的变化可能与理解戈谢病病理学有关。